The long-term goal for this project is to determine the epithelial ion transport pathways and the associated regulatory mechanisms within the distal male genital tract in order to provide a basis for better understanding reproductive dysfunction. Ion transport processes within the distal ductus deferens (dDD) have not been clearly identified although errant ion transport within the duct is clearly associated with asthenozoospermia, oligozoospermia, non-obstructive azoospermia, and obstructive azoospermia. Recent observations point to a novel constellation of Na+-dependent ion transport pathways within the dDD. The cellular and molecular basis of these observations remains to be determined. We hypothesize that specific cells in dDD epithelium are capable of regulated Na+-dependent HCO3- secretion and/or Na + absorption. These processes may occur independently in separate cell populations or may be simultaneously expressed in a single cell population. The epithelial model that is proposed represents a paradigm shift from currently held views regarding dDD function. This new epithelial model provides for neurotransmitter-dependent mechanisms to acutely alkalinize the lumen for sperm activation just prior to ejaculation and provides a basis to account for male factor infertility that is currently diagnosed as 'idiopathic.' Modem electrophysiological, biochemical, cytochemical, and molecular techniques will be employed to study native epithelium along with primary cell cultures to delineate the mechanisms and signaling pathways that contribute to epithelial function with the ultimate goal of modulating male fertility. The hypotheses will be tested by addressing the following specific aims. Aim 1. To identify key mechanisms that contribute to HC03 transport across distal ductus deferens pithelia. Aim 2. To identify key mechanisms that contribute to Na vtransport across distal ductus deferens epithelia. Results from these studies will lead to an increased understanding of male reproductive tract function along with a more complete understanding of Nav and HCO3 transport mechanisms in general. The proposed studies will ultimately benefit the medical community by providing rational bases for therapeutic interventions both to treat male infertility and to modulate male fertility (i.e., male contraception).